Human pituitary adenomas represent the most common intracranial neoplasm. Approximately a third of diagnosed pituitary tumors do not hypersecrete hormones, therefore classified as clinically non-functioning adenomas (NFAs). These tumors usually grow large in size, resulting in neurologic deficit and hypopituitarism in patients. The large majority of NFA are derived from gonadotroph cells and cannot be treated medically. Furthermore, the molecular mechanisms causing NFAs are mostly unknown. Therefore, there is an urgent need to investigate molecular events specifically linked to the development of these tumors. Using an X- chromosome linked marker, we discovered that NFA cells are monoclonal in nature, meaning that they are derived from a single somatic cell transformed by genetic or epigenetic mutations. Therefore, identification of such mutations and investigation of the function of affected genes will yield insights into the mechanisms of NFA development. By comparing gene expression between normal pituitaries and NFAs, and subsequent investigations, we identified Maternally Expressed Gene 3 (MEG3) as a novel candidate tumor suppressor in the pituitary. MEG3 is highly expressed in normal pituitary. Its expression is lost only in NFAs, partially due to epigenetic silencing of its promoter, not seen in other pituitary tumor types. Re-expression of MEG3 inhibits tumor cell proliferation and xenograft tumor growth. Strikingly, the products of the MEG3 gene are long non-coding RNAs and function through a well-known tumor suppressor p53. Taken together, we hypothesize that MEG3 uses novel mechanisms to suppress the development of human pituitary NFAs. Therefore, the goal of our study is to determine the in vivo function of the MEG3 gene in suppression of pituitary tumors using animal models and unveil molecular mechanisms of MEG3 tumor suppression. In this grant application, we propose to determine 1) the effects of Meg3 inactivation on the development of pituitary tumors in vivo; 2) mechanisms whereby MEG3 lncRNA suppresses tumor growth and 3) the mechanism of p53 activation by MEG3 lncRNA. The discovery of MEG3 non-coding RNA gene as a candidate tumor suppressor is a critical step in understanding the pathogenesis of human NFAs. The investigation of its function in tumor suppression will broaden our knowledge of the involvement of non-coding RNAs in human tumor biology; and provide opportunities to develop novel medical therapies for human pituitary tumors.